The diagnosis of Alzheimer's disease (AD), the most common form of dementia in Western countries, is largely based on historical and clinical criteria. Although many studies report a reasonably high degree of diagnostic accuracy (80-90%), often these studies include patients evaluated at specialized centers with advanced disease. At present, post-mortem examination of brain tissue is the only tool for definitive diagnosis. Therefore, the development of a biomarker for AD would aid greatly in the diagnosis of this disease. In addition, such a marker could potentially be utilized to measure efficacy in future therapeutic trials.
Most studies of AD biomarkers to date have focused on known pathological substrates for the disease. Pathological hallmarks of AD include amyloid plaques and neurofibrillary tangles, both comprised primarily of abnormally aggregated endogenous proteins. Amyloid plaques are extracellular proteinaceous aggregates. They are principally composed of the amyloid-β peptide (Aβ), a 38-42 amino acid peptide fragment of the amyloid precursor protein (APP). The major species, a 42-amino acid peptide (Aβ1-42), is significantly decreased in the cerebrospinal fluid (CSF) of patients with AD. Neurofibrillary tangles are intraneuronal protein aggregates found mainly in neuritis. The neurofibrillary tangles are primarily composed of hyperphosphorylated Tau (pTau), a microtubule-associated protein. Several studies have shown that total Tau (tTau) and pTau are elevated in AD CSF.
Although studies exploring the use of these two biomarkers in the diagnosis of disease have been carried out, the results have not led to a useful, definitive method. Significant overlap in values for these biomarkers between cases and controls limits their utility as diagnostic biomarkers. In addition, several reports have demonstrated the lack of correlation between amyloid plaque load and the degree of dementia, suggesting that the former may not directly relate to the latter. At present, there is a need for an improved tool more reliable than those currently available for the diagnosis of Alzheimer's disease.
Another class of biomarkers that may have utility in the diagnosis of AD, are biomarkers that reflect neuronal death rather than specific markers of disease pathogenesis. Such markers may provide information about disease progression related to functional outcome, and have utility in future clinical trials testing therapeutic efficacy.
An example of such a biomarker is Visinin-like protein 1 (VLP-1), a calcium sensor protein which is expressed in high abundance in neurons of the central nervous system. VLP-1 is elevated in the CSF of rats following transient focal ischemia, and is detectable in elevated concentrations in the plasma of ischemic stroke patients. The use of VLP-1 as a marker for brain damage and for AD has been described in PCT
publication WO 2006/012351. Thus, while VLP-1 indicates brain damage, it has also been identified as a useful diagnostic for Alzheimer's disease. Alternative causes for brain damage are associated with readily identified conditions such as stroke, asphyxiation, invasive surgery and trauma.